1. Field of the Invention
The invention relates to the use of meso-zeaxanthin to increase the deposition of macular pigment in the human eye, and for the therapeutic treatment or prophylaxis of diseases and disorders of the macula, and in particular age-related macular degeneration (AMD).
2. Background Information
The macula is the anatomical region of the retina which in man is responsible for central vision. Centered on the fovea, where the visual axis meets the retina, it extends radially outwards to a distance of about 2.75 mm (Davson, 1990). The macula is divided into the inner macula and the outer macula. The inner macula extends radially out to a distance of 1.5 mm while the outer macula is defined by the surrounding annular ring. The central portion of the macula is easily recognizable because of its yellow coloration which results from the presence of macular pigment.
Despite its small size, the macula is endowed with the highest degree of visual acuity. It is therefore not surprising that considerable effort is devoted to understanding and, when possible, treating diseases which disrupt the nominal functioning of the macula. One such disease is age-related macular degeneration (AMD) which occurs in about 20% of the population above the age of 65 and is the leading cause of visual impairment in the USA and UK. AMD has up to the present time been an irreversible condition.
Pooled extracts of the macular pigment were found by Wald (1945) to have a carotenoid-like absorption spectrum which appeared to match that of lutein. Further work in the 1980's demonstrated that it consisted of lutein and zeaxanthin (Bone et al., 1985).
More recent work (Bone et al., 1993) has shown that the zeaxanthin component found in the human retina is itself composed of all three of the possible stereoisomers. FIG. 1 shows the stereochemical structures of the macular pigment components. The 3' hydroxy groups on lutein and meso-zeaxanthin have the same absolute configuration making interconversion possible by a movement of the 4', 5' double bond (lutein) to the 5', 6' position (meso-zeaxanthin). Of the three stereoisomers, SSZ is present only as a relatively small component. RRZ is of dietary origin whereas RSZ (meso-zeaxanthin) is not common in the diet and is not detected in human serum. It has been suggested that the presence of RSZ may be the result of isomerization of lutein to RSZ by an enzyme.
The function of the macular pigment has not been unequivocally determined. It has been proposed that one function may be to reduce the adverse effect of chromatic aberration in the ocular media thereby increasing acuity (Walls, 1967, Reading and Weale, 1974). A more generally held current view is that the pigment probably acts in a protective capacity against the damaging effects of blue light (Dicthburn, 1973; Kirshfeld, 1982; Bone et al., 1984) which can induce the formation of reactive free radicals within the retina and the formation of such species may be greatly reduced in individuals having a high level of macular pigmentation. The macular pigment may also serve passively as a filter and shield sensitive tissues from harmful excessive blue light.
AMD is a disease that develops gradually over a period of many years with loss of sight being the ultimate result. The damaged tissue has an unusually high lipid content that it has been suggested oxidizes to form lipofuscin, a fluorescent product of lipid oxidation. It has been postulated that exposure of the retina to excessive blue light may increase the rate of lipofuscin formation (Feeney-Burns et al., 1990; Gottsch et al., 1990).
To date, little is known about the factors that influence the uptake of carotenoids into the macula and there is no effective cure or prevention of AMD.
The studies of plasma carotenoids in case control studies of AMD have been equivocal. In the Beaver Dam eye study (Mares-Perlman et al., 1995), no differences were observed between 167 cases and 167 controls in serum including lutein or zeaxanthin. In the Eye Disease Case Control Study Group (1993) results of 421 cases and 615 controls were reported. People with serum carotenoid levels in the medium to high group had one half to one third risk of AMD compared with the low group. All of the carotenoids measured, including lutein, zeaxanthin, beta carotene, alpha carotene and cryptoxanthin were implicated. In a further publication (Seddon et al., 1994), these authors found that the consumption of lutein and zeaxanthin (which are primarily obtained from dark green leafy vegetables) were most strongly associated with a reduced risk of AMD. However, some people with a high consumption of green vegetables still suffered from AMD.
In an abstract published in the March 1995 issue of Investigative Ophthalmology and Visual Science (36, suppl, 892), the carotenoid analysis of 8 normal eyes and 8 eyes from patients with AMD was reported. The results suggested a positive correlation existed between lowered macular pigment and the prevalence of AMD, but recommended that caution should be exercised in this interpretation because the reduced macular pigment could be a result, rather than a cause of the disease. When the subject matter of the above mentioned abstract was submitted for publication to a peer-reviewed journal, the referees recommended rejection because the number of samples analyzed was too small. Further results were therefore necessary before any conclusion could be made on the possible preventative role of lutein/zeaxanthin in AMD.